γ‐Tocopheryl quinone stimulates apoptosis in drug‐sensitive and multidrug‐resistant cancer cells

Abstract

Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.

Gamma-Tocopherol – An Underestimated Vitamin?

“…The effect of Á-tocopherol quinone is mainly related to induce apoptosis in leukemia cells and breast cancer cells [124]. Similar results were obtained by Calviello et al [125], who showed that Á-tocopherol quinone induced apoptosis in a dose-and time-dependent manner in cultured human leukemia HL-60 and colon adenocarcinoma WiDr cells, and in murine thymoma cells growing in vivo in ascites form.…”

Reversion of Multidrug Resistance in a Chemoresistant Human Breast Cancer Cell Line by β-Elemene

“…Recent studies have suggested that the occurrence of MDR in cancer cells may be the result of a decrease in the ability of the cancer cells to initiate apoptosis in response to cytotoxic agents [28]. Previous studies suggested that overexpression of P-gp via transfection of MDR1 in MCF-7/DOX cells has been shown to significantly decrease the apoptotic response to doxorubicin as compared with its effect in wild-type MCF-7 cells [29].…”

Dietary fish oil and vitamin E enhance doxorubicin effects in P388 tumor‐bearing mice

“…Failure to repair these DNA lesions can lead to apoptosis (50). On the other hand, γ-and δ-tocopherol quinones generated from γ-and δ-tocopherols, respectively, are cytotoxic arylating electrophiles because they contain an α,β unsaturated carbonyl structure that forms Michael adducts with compounds containing a thiol nucleophilic group, such as glutathione and proteins (51). Whether treatment with PUFA, tocopherols, and DOX leads to the interactions through their alkylating/arylating activities and thereby enhances therapeutic efficacy remains to be studied.…”